HU229217B1 - A process for the preparation of 1,4,7,10-tetraazacyclododecane - Google Patents

Description

Procedure for the preparation of 1,4,7,19-betahazaclindodecane

The present invention relates to a novel process for the preparation of 1,4,7,1-tetraazazacyclododecane of formula (I) according to Scheme 1.

More particularly, the present invention relates to a process for the preparation of nz 1,7,7-tetraazaeacyclodeodecarb (generally known as Clene) in a manner other than the classical synthesis of Ridnsss-A & ms (e.g. J.A.R. Cfeetn. are used in the preparation of the naphtha salt of formula V of formula (I).

The starting material for the preparation of the macrocyclic chelating agents suitable for the 1,4,7, δ-tetraaza Iodoacetan metal ions, which form very stable complexes with said ions.

Complexes of such starch forming agents with < RTI ID = 0.0 > iron < / RTI > metal ions, especially gadolinium ions, can be used as diagnostic agents in nuclear magnetic resonance (NMR) assays, which would otherwise be unattainable.

Currently, two contrast agents are available commercially under the names Oraem and Prohance, which are eiclene-based gadolinium complexes. Mas complexes are under construction.

There is therefore a need for the production of such building blocks and for the development of processes that can be carried out in a cost-effective manner in the industry.

An economically and environmentally advantageous process for the preparation of the compound of formula (1) should be devised, aaa avoiding the use of standard amine tosyl derivatives used in Richma-Alkins synthesis,

WO 97/49691 discloses the preparation of the compound of formula (II) according to Scheme 2, wherein the formula (H1) isoscahydro-2a, 4s, 6a, 8a-tetraa7.aclclopem (fg] aoenalblene is used as the central intermediate of 0). The intermediate can be prepared by cyclizing 3H, 6H-octalddro2a, 5,6,8a-tetraazacenaphthylene of formula (IV), which in turn has been prepared from tetra-tetraminylxyl and glloxal,

The cleavage of the two carbon atoms typical of the Formula III compound required to produce the compound of Formula I involves oxidation of the compound of Formula I and then converting the oxidized product of Formula III to a compound of Formula I by alkaline hydrolysis.

The aldehyde for oxidative cleavage is described in WO 96/28432 by hydrolysis of the rock-flake compound of Formula (I) by smithbromide or lydroxylamines in ethanol solution while being refined.

WO 98/49151 discloses a preferred process for the preparation of a compound of formula (I) from compounds of formula (III). starting from the hydrolysis in aqueous solution at slightly acidic, neutral or slightly alkaline pH, in the presence of a primary diamine derivative of formula VI, where x is 6-2, Q is -CH ₂ CII (OH) CH, -, - (CH ₂ ) ₃ NH (CH ₂ } ₂ - or - ((CHd ₂ NII) ACHAR) when x is 1 or Q is -CH-- when x value is 2.

Particularly preferred is the diethyl ether triamine as a primary dixrin.

The reaction is carried out in aqueous medium at pH 5 ^:::,> 9, preferably on a pH value of 8 h at OO-'lOO ° C, one mole of compound of formula 2 to 26 moles of (VI) (Π): in the presence of a primary charge, in an inert gas atmosphere or in air, and with a reaction time of 12 to 48 hours.

9SJ 59-4P23 / 8L

X Φ ΦΦ X «X Φ Φ X»

Φ X * χ * »χ -Φ Φ- X

X X X X X Μ Φ X φ Φ X

After completion of the reaction, the solution is basified with a base such as sodium hydroxide, evaporated to a small volume or evaporated and the compound of formula (I) is extracted with a suitable solvent such as toluene, chloroform, buolanolic or analgesic. The organic phase is evaporated to give aysxs (I). a macrocyclic compound which is finally recrystallized from tolnol or ethyl acetate.

The simple combination of the two processes according to Reaction Scheme 4 diffused diffusely in the production of the compound of formula (I) does not seem to be straightforward, and therefore such a process is difficult to implement on an industrial scale.

In addition, WO 97149691 discloses that the compound of formula (III) is extubated with hexane, which results in a reduction in the amount of product during evaporation of the reaction mixture, as the compound is partially removed by the expelled components, and partly by chemical decomposition by the alkylating agent present.

In practice, the cyclization of the reaction of Imageine IV with 2-dichloroethane is preferred but not. selective and by-product alkylating agents are formed during the partial alkylation of the compound of formula (TV), the amount of which is not to be neglected in industrial scale use. These products undergo a mild reaction during evaporation and thus reduce the yield of the compound of formula (HI),

Surprisingly, this problem can be easily avoided by isolating the compound of formula (III) in the form of a salt with a suitable inorganic acid.

It is further found that the isolation of compound (1) in the hydrochloride form improves the industrial yield without reducing the compound of formula (I) in general, since the release of compound of formula (I) from the salt is quantitative.

The present invention therefore relates to a process for the preparation of the 1,4,7,10-fetraacacyclododecone of formula (I) according to the following scheme:

a) condensation of triethyl-methyl-tetramethylamine (TETA) with ghoxal hydroxide in water or a water-miscible solvent or mixture thereof at a temperature of 8-5 ° C and in the presence of stearic acid or a small excess of potassium hydroxide,

b) reacting the resultant compound of formula IV with h 2 -dichloroethane. 1-5 moles per mole (TV), S-10 moles sodium carbonate per dimethylacetate (DMAC) and 1 mole (IU). in the presence of 0.5 to 1.9 moles of sodium chloride per mole of TV compound. At a temperature between 25 ° C and 150 ° C, and the compound of formula (111) obtained is isolated in your body as an acid salt with hydrobromic acid and phosphoric acid,

c) hydrolyzing the compound of formula (1Π) with diethylenetriamine in water at pH-S-9 and at a temperature of 99-1.20 ° C for 1 mole of compound (131) in the presence of 5 to 19 moles of inert air for 12 hours or and the hydrochloride of formula (II) is exposed, and

d) optionally releasing the base of formula I quantitatively.

Step (a) is carried out essentially as described in WO 97/49691.

Step b) is also carried out as described in WO 97/49691, but preferably in WO 97/49691

98/49 with the modification 151,

According to the invention, the formula (TV) condensation of the compound with 3-5 mol of 1,2-dichloroethane per mol of the compound of formula (IV) in the presence of sodium carbonate in the presence of sodium carbonate and

- 3 thiols ί moles of formula (IV)! In the presence of 0.1 to 2.0 moles of sodium bromide per compound, the condensation salt of A is preferably used in the presence of 3 volumes of 1,2-dichloroethane, 10 moles of sodium carbonate and 0.5 moles of sodium bromide.

Surprisingly, we found. that the completion of the reaction and the filtering of the inorganic salt hated the above-mentioned problems can be overcome by adding the acid soluble in dimesulfoceamide and the compound of formula <111) to a salt which is soluble in a dipolar aprotic solvent.

For this purpose, saltwater and hydroacetic acid are preferred.

It has been found that dimethylacetaldehyde is diluted with a mixture of properly diluted (EB) forming compound and 1 mol <RTI ID = 0.0> (fV) </RTI> of the preparation. 2 to 4 moles, preferably 2.4 moles, of 3? addition of about 95% by weight of hydrochloric acid after the reaction is complete. a precipitate is formed.

Further improvement is achieved by using 85% by weight of phosphoric acid instead of 37% by weight of hydrochloric acid, which reduces the amount of solvent required to completely precipitate the compound of formula (IH) in the form of a tertiary salt. The resulting salt is a ditic salt.

It has been found that to precipitate (Hij) compound, based on 1 mol of compound (V)

An additional advantage of using 85 wt% phosphoric acid is that the tip is less water in the system than 37 wt% w / w hydrochloric acid, which is advantageous in the fractional distillation of dimsticreelic acid.

For the isolation of the compound of formula (HI) in the form of the hydrochloride salt, it is preferable to use a mixture of 6 l of dimethyleneethylene per mole of the compound of formula IV, and 4.5 l of dhsehiacetamide per mole of the compound of formula which significantly reduces the amount of solvent required.

Step c) is a hydrolysis, or rather of formula (IH)! deprotection of the compound which is considered to be the glyoxal protected form of compound (Ϊ). This. Steps according to WO 98/49151 are carried out with an amine suitable for irreversible substitution of glyoxol. Diethylene trinmin (DE7A) is particularly preferred as amine.

However, the presence of dfethylene iriatnine makes the formula (I) more difficult. The compound is directly isolated from the hydrolysis mixture by the addition of a base to a highly alkaline pH, crystallization with toluene and extraction of the tartaric acid, and the appropriate temperature at constant concentration.

By this procedure, as shown in the examples, the (HI) / (I) conversion to the crude product is relatively satisfactory for the purification of the pure compound (HI), but the yield of the purified product is about 70% due to impurity DET.A. requires a crystallization step.

The separation of DETA from the reaction mixture is therefore particularly important from a qualitative and quantitative point of view, and the conversion to (111) .- (1) must take into account that the starting material is a crude product.

Surprisingly, it has been found that the final isolation of the compound of formula (1) in the form of its tetrachloride permits greater than 95% isolation of the compound of formula (Ij) from the hydrolysis medium and the isolation is particularly selective for the compound of formula (1). Compound and other impurities which give high purity end product in high yield.

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If desired, the quantitative modification of the tea salt and chlorine salt may be carried out in a manner known per se, for example by reaction with aqueous sodium hydroxide solution and removal of water (e.g., azeotropic distillation with saline), salt filtration and distillation.

The cravings in the crystallization medium can be traced back to the formula (0) and can be recycled without loss. The conversion of <l) * 4HQ / (l>) is therefore quantitatively feasible.

Most preferred for converting the imageine compound 011) into its hydrochloride salt or deprotecting salt into the compound of formula (J) is the molar amount of BHj / DETA 1.5 molar, and the purification of the compound of formula (I) in the tetrachloride is not affected.

The above solution avoids the problems known in the art and therefore the process of the invention is particularly advantageous on an industrial scale.

The invention is illustrated by the following examples without limiting the scope of the invention to the examples.

The following method is used for barrier Krotnatography asaltz:

Device: Hewiett-Paekard 5890 II Elish ready: 7673 with automatic minivevs and HP3365.

Column: HF-ULTRA 1 column, length 25 m. inner diameter 0.32 mm, film thickness 0.52 pm (HP Serial No. 19Ö91A-112).

Heating program: first * flavor engine at 150 ^l, C for 8.5 minutes, then heating at 5 T / min to 185 ° C, second isomer at 18.5 ^e C for 0.01 min, then heating at 20% 7pere 240 ° C to, third. taste 240 X 2 minutes cross.

injector:

detection:

Column Flow: Conveying Gas; injection

Sample Concentration:

(ratio 1: δ); flow rate: speed 72 nti / min, heat setSet 200% ·, insert (HP number 13740-80190) with glass wool (Chrosnpaek number 8490), stationary phase Chrontösorb W HP, 0.149-0.17? mat (Supelco No. 2-0153).

FID, temperature 290X.

1.2 ml / min.

Shell.

ni.

10-20 mg / ml water.

Preparation of Xalaa (I)

A) Purification of the iDeómoomgü ^ rXJETÁ)

A reactor was charged with 5 kg of crude tridylene cup under a purging atmosphere and then 800 g of a liter of nitrogen were added under stirring under a nitrogen atmosphere. water was added over 8 minutes, keeping the internal temperature below 45 ° C.

The reaction mixture was adjusted to 35 ° C, then added with pure TCTA straight-chain hydrogen, stirred for 1 hour and diluted with 10 L of toluene over 20 minutes. The reaction mixture was heated to 40 ° C and subjected to a reflux temperature of 25 ° C for 30 minutes and maintained at this temperature for 38 minutes.

The precipitate was filtered, washed foiuoílal and shank 24 hours under static száriíőbaa ^(y 30 C) under vacuum (2 kPa). 3.71 kg of the desired product are obtained.

Yield: 89% (water-saturated state) · per linear isomer contained in the starting mixture;

Gas chromatography: $ 8.22% (peak area);

Water content (Kari Fiseher): 20.75%.

B.) Preparation of IV Compound

3.71 kg of straight branched TETA hydrates are charged into a reactor under a stream of hydrogelated atmosphere, 20 'kg of water and 2.9 kg of tetrecimtefoloxide. The resulting slurry was stirred under a hydrogen atmosphere, cooled to 0-5 ° C, and maintained at this temperature by the addition of 9% aqueous glyoxapholafe, diluted with 2.9 kg of a 4% by weight solution of water.

After completion of the addition, the reaction mixture was kept at 5 ° C for 1 hour, and then a centrifuge was washed with water (1 kg) and stirred for 15 minutes. The catechol hydroxide was filtered off. The filtrate was concentrated to dryness under reduced pressure in a rotary vacuum. The obtained products were used directly without further purification.

Occupancy: 98.5% (anhydrous):

Gas chromatography flash chromatography 95.5% (peak area);

Water content (Kari Fiseher): 0.24% "

A reactor was heated to 40 ° C and a solution of 3.48 kg of the above compound of formula (IV) in 8 µl dimethylacetanide batt was heated under nitrogen. 11.6 kg of W> C0yNsBr 10: 1 are mixed in a micronized mixture and 5.94 kg of 1.2 ~ dichloro are introduced. The reaction mixture was heated to 80 ° C for 3 hours, then cooled to 25 ° C, filtered, and the salt. 16 1 wash with dsnetitacetarsiddal. Is returned to the A &lt; RTI ID = 0.0 &gt;

The reaction mixture was maintained at 26 ° C and 4.61 kg of 85% phosphoric acid was added dropwise under nitrogen. The reaction mixture was stirred at this temperature for 2 hours and then allowed to stand overnight. The precipitate was filtered off and washed with 10 L of isopropanol. The product was dried in a static dryer in vacuo to give 2 kg of the compound (III) as a crude product (65% w / w phosphate) in 58% yield.

To a rector under nitrogen atmosphere, 2.0 kg of a crude solution of the phosphate salt of the compound of formula (I) in 14 kg of water was added, then 5 kg of diethyl ether was added rapidly and the mixture was adjusted to pM-7 with 34% hydrochloric acid. The reaction mixture is refluxed under nitrogen for 2.4 hours with stirring, then cooled to 25 ° C and added with 1 kg of 34% hydrochloric acid. The resulting solution is made up to 30 kg under reduced pressure.

An equal amount of 34 wt% hydrochloric acid was added, the mixture was stirred at 25 93 for at least 2 hours, then left overnight. The precipitate was filtered and washed with 2 wt% hydrochloric acid. The resulting 4 kg precipitate was dissolved in 5 kg of water at 60 ° C, the portions were filtered off at this temperature due to photofeed, and the solution was charged to a reactor heated to 50 ° C. 7.15 kg of 34% hydrochloric acid are added over 1 hour and the mixture is stirred at the indicated temperature. The reaction mixture is then heated to 20 ° C.

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- 6, filter, wash with 2X hydrochloric acid, then wash the absorber with ethanol. It is then vacuum-dried in a static dryer. This gives 2.3 kg of crystalline compound of formula (I) (yield: 36, i% (&gt;) (IV)). Gas chromatography: 99.89% (peak area), water content (Kari Eiseher): 0.18%, acid twin (0.1 H NaOB) t 98.9%, argentimetric titer (0.1 N AgNO 3); 99.98%, Complexometric liter (,, 1N ZnSOa): 98.6%, Az * H. Nuclear Magnetic Resonance Spectrum NMR, Al'-NMR.

Example 2 Isolation of a compound of formula (IH) as a crude hydrochloride salt

The hydrochloride salt of the compound of formula (III) was prepared essentially as described in Example 1, Step C, except that no final drying was performed using concentrated hydrochloric acid instead of phosphoric acid. The wet product was not dried at the end of the isolation. to determine the amount of compound of formula. Different isolation! The results obtained in the case of x-rays are given in Table L.

Table I: Compound of Formula IV: DMAC HCl / Yield

(Kg) (Mol) (Ϊ) (Mol) (%) 0.64 3.9 22.4 2.41 46 2.5 15 90 2.41. 51 2.5 15 90 2.41 49

3, .example Compound of Formula III Isolate Compound of Formula IV • in the form of its crude phosphate salt Table II Yield: (%) © MAC Π) B _? PO "(IV) (mole) (Kg) (Mol) 0.33 2 12 2.4 53 0.98 2 36 2.4 52 0.90 5.5 54 1 41 2.5 15 67.5 * 5 THE. 58 2.5 15 67.5 4 49

Szsbadalml Requirements

Claims (8)

1. A process for the preparation of a 1,4,7,10-tetraazycyclic acid compound of formula (I), wherein: (a) the sterilization stream is condensed with glyoxal hydrate in water or in a water-miscible solvent or both. at a temperature of 0-5 ° C in the presence of a stoichiometric amount or a small excess of clomidic hydroxide, b) reacting the resulting compound of formula (TV) with 1 to 5 moles of dimethylbleachamide per 1 mole of compound of formula IV. and 5 to 10 moles of sodium carbonate per mole of Formula (I), followed by 1 mole of Sodium carbonate per mole of Formula (W) at a temperature between 25 and 150 ° C, whereby the compound of Formula (III) is added. we get, e) hydrolyzing the compounds of formula (ffl) by reaction with dehydrodiamine in water at pH 5-9 to 90-120 ° C, based on 1 mole of compound of formula (III) in the presence of 5-10 moles of lithium gas in an atmosphere of 12 hours, and the tetral hydrochloride of formula (Si) is exposed, and d) if desired, releasing the base <1> quantitatively, wherein the compound of formula III obtained at the end of step h) is isolated in the form of a salt with an inorganic acid selected from hydrochloric acid and phosphoric acid. A process according to claim 1, wherein step (b) is carried out by condensation of the imageine compound (IV) with 3 to 5 moles of 1,2-dichlorobenzene per 1 mole of the compound of formula (IV) and in the presence of sodium kebonate. 0.1 to 2.0 moles of sodium bromide per mole of the compound of formula IV as a catalyst. The process according to claim 2, wherein the goat is using 3 moles of 1,2-dichloroethane, 1 mole of sodium crown and 0.5 mole of sodium bromide per liter (N). 4. 1-3. A process according to any one of claims 1 to 4, wherein the reaction mixture obtained in step b) is pressed with 2 to 4 moles of concentrated hydrochloric acid per mole of (TV). The process of claim 4, wherein the concentration of the reaction mixture is 1 mol of a compound of formula (IV): 1 dimethyloacetamide. 6. A process according to any one of claims 1-3, wherein 85% phosphoric acid is added to the final reaction mixture obtained in step b) at least 2 moles per I mole of the compound (TV). 7. His. The method of claim 1, 000 / analyte, leaves a. reaction mixture per liter of compound (IV) contains 4.5 liters of dimethylectamide. The process according to any one of claims 1-7, wherein the ratio of salt of the compound of formula (HI) to the charged salt in step c) is 1: 5.